1. Antimicrobial Agents
Antimicrobial agents are chemical compounds that either destroy microbes, prevent their pathogenic action, or prevent their growth. Antimicrobial agents, often referred to as anti-infective agents, are frequently applied topically to the skin and mucous membranes in the form of a solution, cream, or ointment; appropriate formulations may be applied to wounds and body cavities, and to the eyes, nose, and mouth.
In general, topical antimicrobial agents are directed at bacteria, viruses, and fungi. They have been used successfully in the prevention and treatment of a number of infections, including impetigo, candidiasis, tinea pedis (athlete's foot), acne vulgaris, and infections resulting from burns and surgical wounds.
Most agents have a limited spectrum of activity. For example, some are specific for particular gram (+) organisms, while others are specific for particular gram (-) organisms. Moreover, bactericidal agents typically are not fungicidal, while fungicidal agents typically are not bactericidal.
In addition, due to the widespread use and frequent over-prescribing of antimicrobial agents, there is an increasing incidence of microbes acquiring drug-resistance. In other words, a microbe that was once susceptible (i.e., inhibited or killed) to a particular antimicrobial agent is no longer susceptible. This is especially important with regard to bacteria.
Acquired drug resistance is usually caused by a mutation within the genome of the microbe or by the acquisition of a plasmid. For example, one of the major mechanisms of resistance to the .beta.-lactam antibiotics, including penicillins, is the production of .beta.-lactamases. Moreover, resistance to one member of a class of agents (e.g., the aminopenicillin ampicillin) can result in complete cross-resistance to other members of that class (e.g., the aminopenicillin amoxicillin).
II. Topical Silver-Containing Agents
A. Currently Used Therapeutic Agents
Two formulations containing silver have been utilized for therapeutic purposes, silver nitrate and silver sulfadiazine. As set forth hereafter, each is associated with potentially severe adverse effects and other limitations.
A 1% silver nitrate ophthalmic solution can be used in newborns for the prophylaxis of gonococcal ophthalmia (gonococcal ophthalmia neonatorum). Because the silver ion is precipitated by chloride, the silver nitrate solution does not readily penetrate into tissue. Unfortunately, the silver salts stain tissue black as a result of the deposition of reduced silver; some of the staining may persist indefinitely. Thus, silver nitrate is not used topically for other indications (e.g., impetigo).
Silver sulfadiazine 1% topical cream is routinely used as an adjunct in the prevention and treatment of infection in burn victims. [See U.S. Pat. No. 3,761,590 to Fox, hereby incorporated by reference]. Silver sulfadiazine, produced by the reaction of silver nitrate with sulfadiazine, has been associated with necrosis of the skin. In addition, sulfadiazine may accumulate in patients with impaired hepatic or renal function, requiring in severe cases examination of the patient's urine for sulfonamide crystals. Moreover, patients allergic to sulfa agents may exhibit cross-hypersensitivity with silver sulfadiazine. [See generally, AHFS Drug Information, Gerald K. McKevoy, ed., pp. 1704-05 and 2215-16 (1993)].
B. Newer Antimicrobial Silver-Containing Compositions
One of the reasons why there are few commercially available silver-containing therapeutic formulations is the difficulty of making such formulations photostable. That is, such formulations turn a dark color and frequently lose antimicrobial efficacy upon short-term (e g., 3-4 days) exposure to ambient light.
There have been several recent efforts to produce a silver-containing formulation that exhibits high antimicrobial efficacy and photostability. For example, U.S. Pat. No. 5,326,567 to Capelli, hereby incorporated by reference, describes an antimicrobial composition comprising a stabilizing acyclic polyether polymer, silver ion, and a stabilizing halide. The composition may be used in several manners, including topical application to a subject and incorporation into a medical device.
In addition, a new class of silver-containing agents, the silver thiosulfate ion complexes, has recently been disclosed in U.S. Pat. No. 5,429,819 to Oka el al. (hereafter "the Oka Patent"), hereby incorporated by reference. [See also Tomioka et al., "Synthesis of Antimicrobial Agent Composed of Silver-Thiosulfate Complex Ion," Nippon Kagaku Kaishi 10:848-50 (1995)]. The Oka Patent describes an antiviral composition that contains i) a thiosulfate salt and ii) at least one thiosulfate complex salt of a metal and iii) a porous particulate carrier; the metal is either silver, copper or zinc, and the salts are carried on the porous particulate carrier. According to the Oka Patent's teachings, the thiosulfate complex salt and thiosulfate metal complex salt are first prepared as a solution. Thereafter, a porous carrier such as silica gel is impregnated with the solution. Finally, the thiosulfate complex and thiosulfate metal complex salt are immobilized on the porous carrier through drying. This metal-containing porous carrier is then formulated into the compositions described in the Oka Patent.
The antimicrobial compositions taught in the Oka Patent are associated with several notable shortcomings. First, the silver thiosulfate ion complex compositions contain a relatively large concentration of waste salts, resulting from the complexation of a thiosulfate salt, sulfite salt, and a silver salt, and are thus relatively impure. For example, producing 1 part of a silver thiosulfate ion complex using 1 part of silver nitrate (or silver acetate) to 2 parts sodium thiosulfate and/or 2 parts sodium sulfite will result in 1 part waste sodium nitrate (or sodium acetate); the inclusion of these salts results in a lower concentration of silver. Similarly, as indicated above, the silver thiosulfate ion complex requires the use of porous carrier particles; the necessity of these carrier particles limits the concentration of thiosulfate complex salt and thiosulfate metal complex salt. Thus, the amount of porous carrier particles needed to provide silver at antimicrobial concentrations is high, and, as a result, a topical antimicrobial composition would feel gritty and would be irritating to the skin or wound. In addition, if the concentration of thiosulfate complex salt and thiosulfate metal complex salt carried on the porous carrier is too high, the composition may discolor.
Finally, the compositions taught by the Oka Patent cannot be easily incorporated into a polymer matrix at high concentrations. As stated above, incorporation of silver at antimicrobial concentrations requires concomitant incorporation of a large amount of porous carrier. This can cause undesirable changes in the polymer matrix' physical properties (e.g., a hydrocolloid matrix that is stiff and less absorptive). In addition, such incorporation can be unwieldy. For example, in an alginate matrix containing water-insoluble fibers, the silver-containing porous carrier cannot be incorporated into the alginate fibers; as a result, the porous carrier must be mixed loosely within the alginate fibers. Unfortunately, the porous carrier can fall out when the alginate matrix is handled.
From the above, it should be clear that the commercially-available silver-based antimicrobial agents have limited applications and can be associated with severe adverse effects. Moreover, many recent efforts to develop a topical silver-containing formulation are connected with drawbacks, as exemplified by the prior art requirement of a carrier. What is needed is a stable silver-containing antimicrobial composition which is suitable for use in the treatment and prevention of a broad range of infections and that is not associated with the adverse effects and limitations of the agents that have previously been described.